Abstract The cure of HIV using hematopoietic stem cell (HSC) transplant is supported from the experience of the `Berlin patient'. Recent results from patients in London and Dsseldorf are very encouraging and potentially bolster transplant as a cure for HIV. What remains a challenge is to reduce the complexity of hematopoietic stem cell transplant so that it may be more readily adopted in settings that are not acutely life threatening such as chronic HIV disease. Gene editing will make autologous cell transplant possible thereby eliminating the devastating complication of graft versus host disease and address limited availability of allogeneic CCR5 ?32/?32 donors. However, `conditioning' to enable stem cells to engraft the marrow is highly toxic and requires resource intensive hospitalization as currently practiced. We aim to develop nongenotoxic conditioning (NGC) that leverages antibody drug conjugates (ADCs) to specifically target and deplete hematopoietic cell populations as a niche sparing method with reduced toxicity. By investigating ADCs that are HSPC-specific (anti-CD117 targeting) or more broadly immune depleting (anti-CD45 targeting), we aim to identify the optimal NGC strategy for enabling efficient HSC transplant in immunodeficiencies. We will combine our ADC-based conditioning with autologous gene-modified cell transplants in animal infection models to identify a lead strategy with translational value. The specific aims of this project are: Specific aim 1. Optimize the dose and schedule of treating NHP with anti-CD117 ADC to achieve durable donor chimerism. Specific aim 2. Optimize the dose and schedule of treating NHP with anti-CD45 ADC to achieve durable donor chimerism. Specific aim 3. Determine whether nongenotoxic conditioning and gene-modified HSC transplant enable disease control in infected animals. If successful, this project will provide specific interventions that can lower the barrier for gene modified HSC transplantation as an approach to cure HIV/AIDS.